Vaccination is an important tool for handling health care programs both in developed and developing nations. The number of recommended vaccines has increased significantly in recent years against individual infections. The schedule of infants and children may require more than 24-25 separate shots of vaccines for effective immunization against life threatening diseases, as of now.
A combination vaccine which can provide immunogenicity against large number of diseases is always advantageous over the monovalent vaccines. We cannot reduce the number of immunizations required in infants and children to protect them from various fatal diseases but the compliance can be increased by reducing the number of separate vaccinations. A combination vaccine is advantageous over monovalent vaccine as it not only increases the compliance but it is also cost effective and convenient thereby reducing the chances of missing any vaccination shot. However, due to complications associated with the preparation of such combination vaccines like stability of such combination vaccines due to possible interaction between the antigens has always been a challenge before the scientist community.
Hence, the current global scenario calls for a more-effective, acceptable, cost effective and reliable method for immunization against many fatal diseases. The availability of combination vaccines containing protective antigens against majority of diseases, for which universal immunization is recommended in infancy, helps in simplifying the implementation, increasing the acceptance, reducing the global cost of immunization programs and improving disease control. Therefore, cost, convenience and compliance factors contribute to enhanced use of combination vaccines over monovalent vaccines. It can also increase the hand-to-reach patients or populations or frequent non-attendees (Rumke, 1994).
The development of multivalent vaccine capable of protecting against diphtheria (D), tetanus (T), pertussis (P), poliomyelitis, hepatitis B and Haemophilus influenzae type b (Hib) has been an evolutionary process which started in the 1950s when diphtheria and tetanus toxoids were first multivalent with inactivated whole cell pertussis(wP) vaccine (Mallet et al; 2004). Use of detoxified and inactivated pertusis toxin and filamentous hemagluttinin (PT+FHA) as acellullar pertusis vaccine components has been described in Robinson, A., Gorrige, A. R., Funnell, S. G. P., and Fernandez, M. (1989). Serospecific protection of mice against in infection with Bordetella pertussis. Vaccine 7: 321-324. Vaccines combining diphtheria-tetanus-pertussis antigens are available and widely used for over 60 yrs. Expanded quadrivalent and pentavalent combination vaccines also have been developed that include Haemophilus influenzae type b vaccine. Pentavalent combinations that include DPT-Hib-Hepatitis B (HB) are used in several developed and developing countries.
Some of the multiple component vaccines commercially available till date are mentioned as under.
Tripedia® by Sanofi Pasteur is a diphtheria, tetanus, and acellular pertussis (whooping cough) (DaPT) vaccine. It is approved by FDA for use in infants and children under the age of seven. It is also approved to be mixed together with ActHIB®, a Haemophilus influenzae type b vaccine (Hib vaccine), for children 15 to 18 months of age (Trihibit®).
Daptacel® also by Sanofi Pasteur is a diptheria and tetanus toxoids and acellular pertussis vaccine adsorbed (DaPT), approved for routine immunization in infants and children six weeks through six years of age. It is administered via intramuscular injection in four consecutive doses of the five dose immunization series. The four doses are given at approximately two months, four months, six months and six months after the third dose.
A vaccine Kinrix® for DaPT-Inactivated Polio Virus (IPV) has been marketed outside the United States since 1996 which is equivalent to getting the DTaP and IPV vaccines as separate shots with the MMR booster at the 4 to 6 years age of a child.
Pentavalent vaccines to mention are Pediarix® [Diphtheria and Tetanus Toxoids and Acellular Pertussis adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine Combined] and Pentacel® a DTaP-IPV/Hib vaccine that has been used since 1997 as combined vaccine shots to be administered to children as a four dose series, with the primary doses at two, four, and six months, and a booster dose at 15 to 18 months.
Infanrix® hexa by GlaxoSmithkilne, administered intramuscularly, is a diphtheria, tetanus, acellular pertussis, hepatitis B (HB), inactivated poliomyelitis and Haemophilus influenzae type b (Hib) conjugate vaccine, indicated for primary and booster vaccination of infants. Infanrix hexa should be administered as a two- or three-dose primary vaccination course in infants aged less than or equal to 6 months, followed by booster vaccination between 11 and 18 months of age, with an interval of at least 6 months between the last dose of primary vaccination and the booster dose. A detailed study on Immunogenicity and safety of a new liquid hexavalent combined vaccine compared with separate administration of reference licensed vaccines in infants was published by Mallet E, Fabre P, Pines E, et al. Pediatr Infect Dis J 2000; 19:1119-27. Thus, Hexavalent vaccines have been used in several European countries as well as in US which can provide immunization only against six important childhood diseases with single injection. It is desirable that a combination vaccine must include further antigens than hexavalent antigens so that a single vaccination may include immunization against other serious diseases for example rotavirus.
Rotavirus is the leading cause of severe diarrhea disease in infants and young children worldwide. About 600000 children die every year from rotavirus infection, with more than 80% of all rotavirus related deaths occurring in resource poor countries in south Asia and sub-Saharan Africa. The present invention teaches a novel combination of D-aP-T-Hib-HepB-IPV and inactivated rotavirus antigens (IRV) in a stable heptavalent combination vaccine composition.
All rotavirus vaccines that have entered clinical trials in children have been live oral strains and several of these have proven effective and become licensed. However, none of these vaccines have been tested in the target population in poor countries of Africa and Asia where rotavirus remains a prime killer of children. However substantial setback for the oral live vaccine cause adverse events like intussception and the rotaviruses exhibit enormous diversity (Human vaccines 4:3, 143-147:2008). In the present invention we have also pursued an alternative strategy to develop inactivated rotavirus vaccine (IRV) and this rota antigen as part of a combination childhood vaccine with combined sabin type I, II, and III antigen as a novel divalent combination vaccine. The cell line used for the propagation of the rotavirus is vero cells, because this cells have a broad sensitivity to various types of viruses and widely used in human viral vaccine production. Rotavirus vaccines are not available in the prior art as injectable vaccine still now. All rotavirus vaccines available are administered orally. Therefore, it is desirable to include a rotavirus antigen that would confer immunity against any strains of rotavirus in an injectable form in combination with other antigens.
WO1993/024148 discloses an invention of multivalent vaccine containing antigens IPV-DPT-Hib-Hepatitis B wherein DTP is adsorbed to Aluminium Hydroxide or Aluminium Phosphate and Hib is adsorbed to only Aluminium Phosphate, wherein the Hib antigen is used extemporaneously by mixing to the other antigens just prior to the administration. WO1997/00697 discloses a DPT-Hib and pertusis multivalent vaccine adsorbed to aluminium phosphate, in which one container has a freeze-dried vaccine and the other container comprises a second antigen.
WO1998/000167 discloses a D-T-aP-IPV-Hib antigen vaccine and WO1999/13906 describes a multiple component vaccine in which certain components may be reconstituted from a lyophilized state by the other components of the vaccine, or may exist in a single solution, and administers the vaccine in a specially designed container at the time when the vaccination is performed.
WO2000/07623 describes a multi-component vaccine composition having acellular pertussis vaccine components (PT and FHA), diphtheria toxoid (DT), tetanus toxoid (TT), a conjugate of a capsular polysaccharide of (Haemophilus influenze) type b and tetanus toxoid or diphtheria toxoid (Hib), Hepatitis B Surface Ag (HBsAg) and inactivated poliovirus (IPV) which may be in a single solution, or certain components may be reconstituted from a lyophilized state by the other components of the vaccine. WO2002/000249 discloses a capsular polysaccharide of H. influenza b not adsorbed onto an aluminium adjuvant salt, and two or more further bacterial polysaccharides which may include whole cell pertussis, tetanus toxoid, diphtheria toxoid, Hepatitis B surface antigen (HbsAg), and/or conjugate polysaccharides of N. meningitides type A, or B, or C as antigens in a single quadrivalent and/or trivalent vaccine. WO2006/097851 discloses a multivalent vaccine which can be prepared extemporaneously at the time of use by mixing together two components the first component comprising D, T, wP and HBsAg antigens and a second component comprising a Hib conjugate and one or more meningococcal conjugates. WO2007/054820 relates to a vaccine composition wherein the D, T, and aP antigens are specifically adsorbed on aluminum hydroxide and the Hib and the Hep B antigens are adsorbed onto aluminium phosphate which do not exist in a fully liquid stable composition.
U.S. Pat. No. 6,333,036 talks about a multivalent vaccine which uses Hib conjugate polysaccharide polyribosylribitol phosphate (PRP) adsorbed to aluminium phosphate including D,T, and aP antigens. The Hep B antigen is adsorbed to aluminum hydroxide and the same is not a fully liquid composition to form a multivalent vaccine.
European Patent 1028750 teaches a multivalent vaccine which has the D, T, aP adsorbed to aluminium phosphate and the Hep B antigen not being adsorbed to aluminium hydroxide and also does not exist in a single stable liquid composition to form a combined vaccine.
Although the eradication of poliomyelitis from the western world, and its global decline, is a result of successful use of oral polio vaccine (OPV) in most parts of the world (Plotkin, 1995), the potential risk of vaccine associated paralytic poliomyelitis (VAPP) with OPV, has led many countries to switch over to using IPV for routine immunization. Some other prior art publications in the field are Plotkin SA. Inactivated poliomyelitis vaccine for the United States: a missed vaccination opportunity. Pediatr Infect Dis J 1995; 14:835-9 and Rümke HC. Are different combined vaccines needed in different parts of Europe? A point of view from a Northern European country. Biologicals 1994; 22:425-7. All the patent applications detailed above have different adjuvant to different antigens, and is not present as a single liquid composition in a single vial.
WO2008/044611 discloses a method for the preparation of a mixed IPV-DPT vaccine comprising an inactivated poliovirus Sabin strains type I, II, and III grown in Vero cells, a protective antigen against Bordetella pertussis, a diphtheria toxoid and a tetanus toxoid, which involves the step of producing a poliovirus Sabin strain having a high titer.
All the patent applications mentioned above require reconstitution of the individual components prior to administration of the vaccine. They may not be called combined in the literary sense of the term yet, may be called as a multivalent vaccines to confer immunity against at the maximum of six antigens. The mixing of antigenic components prior to administration from different vials results in diminishing of the antibody titer against any particular antigen owing to interference of antigenic interactions. US publication 2011/0206726A1 teaches a fully liquid hexavalent combination vaccine comprising D-T-aP-IPV, -Hep B and Hib antigens wherein Hib is not substantially adsorbed to any adjuvant and D-T-aP adsorbed to aluminum hydroxide and Hep B adsorbed to aluminium phosphate in a single vial. It also specifies that, antigenic competition in such multivalent vaccines often results in a diminished response to certain individual antigens. The patent application recognizes an inherent problem of mixing of lyophilized vaccines with liquid vaccines which represents supplementary constraint for the practitioner and involves a possibility of the same being carried out badly. It also recognizes that the usage of multi-compartment syringes having separate chambers for liquid and lyophilized vaccines is too difficult to execute and no reduction in production costs of the vaccine is possible, thereby no reduction in the cost of immunization also. Although this application describes a liquid combination vaccine in a single vial, it does not describe a combined vaccine composition containing as much as 7 different antigens. It does not talk about conferring protection or immunity to infections caused by rotavirus in the combined vaccine composition.
Hence, in this invention, it has been made possible to develop such a combination heptavalent vaccine which could be able to provide protection against poliovirus, rotavirus, Haemophilus influenzae, Hepatitis B, Diptheria, Tetanus and acellullar Pertussis by administration using a single combined vaccine. The present invention overcomes the limitations of the prior art by providing a stable, combination heptavalent vaccine (Inactivated poliovirus (Sabin)—Inactivated rotavirus—Haemophilus influenzae type b—Hepatitis B surface antigen—Diptheria-Tetanus-Pertussis(aP)) which permits vaccination against poliomyelitis, rotavirus, Hib, hepatitis B, diphtheria, tetanus and pertussis by single injection which is stable and fulfills the cirteria of effective seroprotection against each of the antigens with minimal or least antigenic interference in the combined vaccine.